Project Summary/Abstract A fundamental goal of research focused on the pathophysiology of Parkinson?s disease (PD) is to understand how environmental and genetic factors implicated in PD contribute to its development and its course. Functional modifications to the genome that do not involve a change in the DNA sequence, known as epigenetic changes, have proven to be a powerful mechanism by which environmental exposure can impact gene expression. Histone deacetylases (HDACs) are a family of epigenetic enzymes that regulate gene expression in the human brain by chemically modifying chromatin, the network of proteins and DNA in chromosomal structure, in response to life experience and the environment. In PD, histone acetylation is markedly increased in midbrain dopamine neurons, in association with down-regulation of multiple HDACs. The neurotoxin MPTP recapitulates these findings, providing a mechanism by which environmental factors may contribute to PD pathogenesis. Furthermore, HDAC inhibitors have had therapeutic success in PD models. These observations raise the possibility that HDAC levels will be regionally altered in PD, reflecting both the topography of pathology in the brain and the severity of clinical impairment. Until recently, the levels and distribution of HDACs in the brain could not be quantified until after death. The development of [11C]Martinostat, the first radiotracer that labels HDACs in living humans, has now made this possible. [11C]Martinostat shows specific HDAC binding with low nanomolar affinity and is under active study in the healthy elderly and several patient populations. The overall goals of this proposal are to evaluate brain HDAC levels and regional distribution with [11C]Martinostat in well-characterized patients with PD, and to explore the relation of regional [11C]Martinostat binding to indices of motor and cognitive impairment. Subjects with early and advanced PD will undergo standardized neurological examination, detailed neuropsychological testing, and combined [11C]Martinostat PET-MRI, and will be compared to previously acquired clinical and PET data of an aged-matched NC cohort to test the following hypotheses: (1) The order of global brain HDAC expression will increase from NC to early PD to advanced PD; (2) Changes in the distribution of HDAC levels detected with PET will correlate with the known topology of pathologic changes in PD, including dopamine cell loss and striatal denervation and regional alpha-synuclein accumulation according to Braak staging (early nigra, entorhinal cortex, anterior cingulate; with later frontal, temporal, occipital, and parietal cortex); (3) Asymmetry of striatal HDAC accumulation will correlate with asymmetry of motor impairment; (4) Global cortical HDAC levels in PD will correlate with global cognitive impairment, with lower levels in cognitively normal PD and NC than PD-MCI and PDD; (5) Hallucinations in PD subjects will be associated with elevated HDAC levels in occipital cortical regions. Together, these efforts will clarify the contribution of dysregulation of epigenetic control of gene expression in PD and will establish the potential for developing [11C]Martinostat PET imaging as a PD biomarker and diagnostic tool.